scholarly journals Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity reduces lung inflammation

2021 ◽  
Author(s):  
Koen K.A. Van Rompay ◽  
Katherine J. Olstad ◽  
Rebecca L. Sammak ◽  
Joseph Dutra ◽  
Jennifer K. Watanabe ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Virus Replication ◽  
Lung Inflammation ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
High Titer ◽  
Natural Infection ◽  
Hospitalized Patients ◽  
Controlled Trials ◽  
The Future

ABSTRACTEarly in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.Author summaryThe results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.

scholarly journals Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

2008 ◽  
Vol 180 (4) ◽  
pp. 2385-2395 ◽  
Author(s):  
Timothy D. Carroll ◽  
Shannon R. Matzinger ◽  
Meritxell Genescà ◽  
Linda Fritts ◽  
Roxana Colòn ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Induced Expression ◽  
Influenza Virus Replication

scholarly journals Exogenous IFN-alpha Administration Reduces Influenza A Virus Replication in the Lower Respiratory Tract of Rhesus Macaques

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e29255 ◽  
Author(s):  
Shannon R. Matzinger ◽  
Timothy D. Carroll ◽  
Linda Fritts ◽  
Michael B. McChesney ◽  
Christopher J. Miller
Keyword(s):  
Respiratory Tract ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Lower Respiratory Tract ◽  
Influenza A ◽  
Rhesus Macaques ◽  
Ifn Alpha

scholarly journals Comparative kinetics of SARS-CoV-2 anti-spike protein RBD IgGs and neutralizing antibodies in convalescent and naïve recipients of the BNT162b2 mRNA vaccine versus COVID-19 patients

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ioannis P. Trougakos ◽  
Evangelos Terpos ◽  
Christina Zirou ◽  
Aimilia D. Sklirou ◽  
Filia Apostolakou ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Natural Infection ◽  
Severe Disease ◽  
Vaccination Campaign ◽  
Hospitalized Patients ◽  
Peripheral Blood Mononuclear ◽  
Post Vaccination ◽  
Antibody Titers

Abstract Background Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. Methods Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). Results We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. Conclusions These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection. Graphical abstract

scholarly journals SARS-CoV-2 binding and neutralizing antibody levels after vaccination with Ad26.COV2.S predict durable protection in rhesus macaques

2021 ◽  
Author(s):  
Ramon Roozendaal ◽  
Laura Solforosi ◽  
Daniel Stieh ◽  
Jan Serroyen ◽  
Roel Straetemans ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Preliminary Evidence ◽  
Correlates Of Protection ◽  
Antibody Titers ◽  
Antibody Levels ◽  
The Relationship

The first COVID-19 vaccines have recently gained authorization for emergency use.1,2 At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4 and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5 Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8 and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.

scholarly journals Severe Acute Respiratory Syndrome Coronavirus Infection of Golden Syrian Hamsters

2005 ◽  
Vol 79 (1) ◽  
pp. 503-511 ◽  
Author(s):  
Anjeanette Roberts ◽  
Leatrice Vogel ◽  
Jeannette Guarner ◽  
Norman Hayes ◽  
Brian Murphy ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Respiratory Tract ◽  
Virus Replication ◽  
Neutralizing Antibodies ◽  
Antiviral Agents ◽  
Small Animal ◽  
Pulmonary Tissue ◽  
Syrian Hamsters ◽  
Significant Pathology ◽  
Coronavirus Infection

ABSTRACT Small animal models are needed in order to evaluate the efficacy of candidate vaccines and antivirals directed against the severe acute respiratory syndrome coronavirus (SARS CoV). We investigated the ability of SARS CoV to infect 5-week-old Golden Syrian hamsters. When administered intranasally, SARS CoV replicates to high titers in the lungs and nasal turbinates. Peak replication in the lower respiratory tract was noted on day 2 postinfection (p.i.) and was cleared by day 7 p.i. Low levels of virus were present in the nasal turbinates of a few hamsters at 14 days p.i. Viral replication in epithelial cells of the respiratory tract was accompanied by cellular necrosis early in infection, followed by an inflammatory response coincident with viral clearance, focal consolidation in pulmonary tissue, and eventual pulmonary tissue repair. Despite high levels of virus replication and associated pathology in the respiratory tract, the hamsters showed no evidence of disease. Neutralizing antibodies were detected in sera at day 7 p.i., and mean titers at day 28 p.i. exceeded 1:400. Hamsters challenged with SARS CoV at day 28 p.i. were completely protected from virus replication and accompanying pathology in the respiratory tract. Comparing these data to the mouse model, SARS CoV replicates to a higher titer and for a longer duration in the respiratory tract of hamsters and is accompanied by significant pathology that is absent in mice. Viremia and extrapulmonary spread of SARS CoV to liver and spleen, which are seen in hamsters, were not detected in mice. The hamster, therefore, is superior to the mouse as a model for the evaluation of antiviral agents and candidate vaccines against SARS CoV replication.

scholarly journals Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

2009 ◽  
Vol 90 (2) ◽  
pp. 488-499 ◽  
Author(s):  
Sandrine Souquière ◽  
Richard Onanga ◽  
Maria Makuwa ◽  
Ivona Pandrea ◽  
Paul Ngari ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Viral Loads ◽  
Cell Counts ◽  
Immunodeficiency Virus

The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4+ T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4+ or CD8+ T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4+ T-cell depletion, in the context of higher levels of CD4+ and CD8+ T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

scholarly journals Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

2021 ◽  
Author(s):  
Shiyu Sun ◽  
Yueqi Cai ◽  
Tian-Zhang Song ◽  
Yang Pu ◽  
Lin Cheng ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigen Processing ◽  
Rhesus Macaques ◽  
High Titer ◽  
Low Cost ◽  
High Dose ◽  
Cross Presentation ◽  
Cell Responses ◽  
Generation Vaccine ◽  
Sterilizing Immunity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.

scholarly journals Zika virus-like particle vaccine protects AG129 mice and rhesus macaques against Zika virus

2021 ◽  
Vol 15 (3) ◽  
pp. e0009195
Author(s):  
Lo Vang ◽  
Christopher S. Morello ◽  
Jason Mendy ◽  
Danielle Thompson ◽  
Darly Manayani ◽  
...  
Keyword(s):  
Zika Virus ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
High Titer ◽  
Neutralization Assay ◽  
Dose Titration ◽  
Development Programs ◽  
Structural Protein ◽  
Virus Like Particle

Background Zika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV. Methodology/Principle findings We have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge. Conclusions/Significance These studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

scholarly journals A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques

2021 ◽  
Author(s):  
Ahmed O. Hassan ◽  
Friederike Feldmann ◽  
Haiyan Zhao ◽  
David T. Curiel ◽  
Atsushi Okumura ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Lower Respiratory Tract ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Angiotensin Converting Enzyme 2 ◽  
Cell Responses ◽  
Vectored Vaccine ◽  
Dose Vaccine ◽  
Intranasal Dose

SUMMARYThe deployment of a vaccine that limits transmission and disease likely will be required to end the Coronavirus Disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) in the upper and lower respiratory tract of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged one month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

scholarly journals SARS-CoV-2 binding and neutralizing antibody levels after Ad26.COV2.S vaccination predict durable protection in rhesus macaques

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ramon Roozendaal ◽  
Laura Solforosi ◽  
Daniel J. Stieh ◽  
Jan Serroyen ◽  
Roel Straetemans ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Preliminary Evidence ◽  
Correlates Of Protection ◽  
Antibody Titers ◽  
Antibody Levels ◽  
The Relationship

AbstractSeveral COVID-19 vaccines have recently gained authorization for emergency use. Limited knowledge on duration of immunity and efficacy of these vaccines is currently available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short-lived, and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection. In this work, we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike protein in rhesus macaques and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We show that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of Spike-binding and neutralizing antibodies, indicating that Ad26.COV2.S could confer durable protection in humans and immunological correlates of protection may enable the prediction of durability of protection.

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